Consumer medicine information

ARX-Sevelamer (was Sevelamer APOTEX)

Sevelamer carbonate

BRAND INFORMATION

Brand name

ARX-Sevelamer (was Sevelamer APOTEX)

Active ingredient

Sevelamer carbonate

Schedule

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What this medicine is used for

Sevelamer is used to treat hyperphosphatemia, a condition caused by too much dietary phosphorus being retained in your body due to a diseased kidney.

Increased levels of serum phosphorus can lead to hard deposits in your body called calcification. These deposits can stiffen your blood vessels and make it harder for blood to be pumped around the body.

Sevelamer helps to remove excess phosphorus that has built up in your body by binding to the phosphorus that is in the food that you eat.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

any medicine containing any sevelamer carbonate
any other similar medicine, such as sevelamer hydrochloride
any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take this medicine if you are pregnant or breastfeeding until you have spoken to your doctor. Your doctor can discuss with you the risks and benefits involved.

Do not take this medication if you have any of the following medication conditions:

hypophosphatemia, a condition where you do not have enough phosphorus in your body
bowel obstruction

Do not give this medicine to a child under the age of 18 years. Safety and effectiveness in children younger than 18 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

swallowing problems
severe constipation
problems with movement in your stomach and bowel
active inflammation of the bowel
undergone major surgery on your stomach or bowel
thyroid problems
you have or have had any other medical conditions

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start taking this medicine.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and this one may interfere with each other. These include:

immunosuppressants, such as cyclosporin, mycophenolate mofetil and tacrolimus – the effects of these medicines may be reduced by sevelamer
ciprofloxacin, an antibiotic used to treat some bacterial infections
medications for thyroid, such as levothyroxine – your doctor may need to monitor the levels of thyroid stimulating hormone (TSH) in your blood more closely
medications for heart rhythm problems
medications for epilepsy

These medicines may be affected by sevelamer or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the directions, ask your doctor or pharmacist for help.

How much to take

The recommended starting dose of sevelamer is 2.4 g to 4.8 g per day to be taken over 3 meals.

For tablets, this means one to two 800 mg tablets with each meal three times a day.

The dose will depend on your serum phosphorus level.

How to take it

Swallow the tablets whole with a full glass of water.

Do not crush, chew or break into pieces.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It is best to take sevelamer with meals.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Sevelamer helps lower your dietary phosphate but does not cure your condition. Therefore, you must continue to take your medicine as directed by your doctor if you expect to lower your phosphate level and keep it down.

If you stop taking sevelamer, your phosphate levels may rise again. It is important to keep taking your medicines even if you feel well.

If you forget to take it

If you miss a dose, take the next dose at the usual time with your meal.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are using this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked. Your doctor will check your progress and monitor your phosphorus levels from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. Your doctor may need to change the dose of your other medicines if you stop taking sevelamer, so you should only stop when your treating doctor tells you to.

Things to be careful of

Due to either your kidney condition or your dialysis treatment you may:

develop low or high levels of calcium in your blood – since this medicine does not contain calcium your doctor may prescribe additional calcium tablets
have a low amount of vitamin D in your blood – your doctor may monitor the levels of vitamin D in your blood and prescribe additional vitamin D as necessary. If you do not take multivitamin supplements you may also develop low levels of vitamins A, E, K and folic acid in your blood and therefore your doctor may monitor these levels and prescribe supplemental vitamins as necessary
develop peritonitis (infection of your abdominal fluid) associated with your peritoneal dialysis – this risk can be reduced by careful adherence to sterile techniques during bag changes. You should tell your doctor immediately if you experience any new signs or symptoms of abdominal distress, abdominal swelling, abdominal tenderness, constipation, fever, chills, nausea or vomiting.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking this medicine.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

vomiting
nausea
constipation
diarrhoea
flatulence
indigestion
abdominal pain

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

rash, itching or hives on the skin
severe constipation

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

Storage and Disposal

Storage

Keep your tablets in their original packaging until it is time to take them. If you take the tablets out of their original packaging they may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store this medicine or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What ARX-Sevelamer looks like

ARX-Sevelamer tablets are white to off-white oval film- coated tablets imprinted with 'R789' on one side and are plain on the other side. AUST R 286648.

Ingredients

This medicine contains 800 mg of sevelamer carbonate as the active ingredient.

This medicine also contains the following:

mannitol
crospovidone
zinc stearate
hyprolose
silicon dioxide
polyvinyl alcohol
purified talc
lecithin
xanthan gum
purified water

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Arrotex Pharmaceuticals Pty Ltd
15 - 17 Chapel Street
Cremorne VIC 3121

Web: http://arrotex.com.au

This leaflet was last updated in October 2023.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

ARX-Sevelamer (was Sevelamer APOTEX)

Active ingredient

Sevelamer carbonate

Schedule

Notes

Distributed by Arrotex Pharmaceuticals Pty Ltd

1 Name of Medicine

Sevelamer carbonate.

2 Qualitative and Quantitative Composition

ARX-Sevelamer film-coated tablets contain 800 mg of sevelamer carbonate.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off-white, oval film-coated tablets imprinted with "R789" on one side and are blank on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

For the management of hyperphosphataemia in adult patients with stage 4 and 5 chronic kidney disease.

4.2 Dose and Method of Administration

Dosage.

Sevelamer carbonate is available as tablets.
Note that powder for oral suspension can be available from other brand/s.
It is recommended to continue monitoring serum phosphorus levels in patients when switching between sevelamer carbonate tablets and powder.
Sevelamer carbonate should be taken in conjunction with a prescribed diet for the management of hyperphosphatemia.
Sevelamer carbonate 800 mg tablets must be taken three times per day with meals at a dosage based on individual patient requirements to control phosphate levels. Tablets should be swallowed intact and should not be crushed, chewed, or broken into pieces prior to administration. Patients should swallow the tablets whole with water.

Starting dose.

The recommended starting dose of sevelamer carbonate is 2.4 to 4.8 g per day based on clinical needs and phosphorus level (Table 1). Sevelamer carbonate must be taken three times per day with meals.

For patients previously on calcium based phosphate binders, Table 2 provides guidance on switching to sevelamer carbonate. Serum phosphorus levels should be monitored to ensure optimal daily doses.

Titration and maintenance.

Serum phosphorus levels must be monitored and the dose of sevelamer carbonate titrated every 2-4 weeks until an acceptable serum phosphorus level is reached, with regular monitoring thereafter. The dose may be increased or decreased by one tablet per meal at two week intervals as necessary (Table 3). Patients taking sevelamer carbonate should adhere to their prescribed diets.

In clinical practice, treatment will be continuous based on the need to control serum phosphorus levels and the daily dose is expected to be an average of approximately 6 g per day.

4.3 Contraindications

Sevelamer carbonate tablets are contraindicated in patients: known to be hypersensitive to sevelamer carbonate or any of the other components of the tablet; with hypophosphataemia; with bowel obstruction.

4.4 Special Warnings and Precautions for Use

General.

The safety and efficacy of sevelamer carbonate have not been established in adult patients with chronic kidney disease not on dialysis with serum phosphorus < 1.78 mmol/L.
The safety and efficacy of sevelamer carbonate in patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders, severe constipation or major GI tract surgery have not been established. Consequently, caution should be exercised when sevelamer carbonate is used in patients with these GI disorders.
Cases of serious inflammatory disorders of the GI tract (including serious complications such as bleeding, perforation, ulceration, necrosis and colitis) with the presence of sevelamer crystals have been reported. Sevelamer carbonate should be re-evaluated in patients who develop severe gastrointestinal symptoms.

Intestinal obstruction and ileus/subileus.

In very rare cases, intestinal obstruction and ileus/subileus have been observed in patients during treatment with sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate. Constipation may be a preceding symptom. Patients who are constipated should be monitored carefully while being treated with sevelamer carbonate. Sevelamer carbonate treatment should be re-evaluated in patients who develop severe constipation or other severe gastrointestinal symptoms.

Fat-soluble vitamins.

Depending on dietary intake and the nature of chronic kidney disease, dialysis patients may develop low vitamin A, D, E and K levels. It cannot be excluded that sevelamer carbonate can bind fat-soluble vitamins contained in ingested food. Therefore, in patients not taking these vitamins, monitoring vitamin A, D and E levels and assessing vitamin K status through the measurement of thromboplastin time should be considered and these vitamins should be supplemented if necessary. In patients undergoing peritoneal dialysis additional monitoring of fat-soluble vitamins and folic acid is recommended, since vitamin A, D, E and K levels were not measured in a clinical study in these patients.
In clinical trials, there was no evidence of reduction in serum levels of vitamins with the exception of a one year clinical trial in which sevelamer hydrochloride treatment was associated with reduction of 25 - hydroxyvitamin D (normal range 10 to 55 microgram/mL) from 39 ± 22 microgram/mL to 34 ± 22 microgram/mL (p < 0.01). Most patients in sevelamer hydrochloride clinical trials received vitamin supplements, which is typical of patients on haemodialysis. Indirect evidence of a reduction in vitamin K levels (an increase in haemorrhage corrected by vitamin K supplementation) was also seen in animals.

Folate deficiency.

There is at present insufficient data to exclude the possibility of folate deficiency during long term sevelamer carbonate treatment.

Swallowing and choking difficulties.

Uncommon case reports of difficulty swallowing the sevelamer carbonate tablet have been reported. Many of these cases involved patients with contributing co-morbid conditions affecting the ability to swallow including swallowing disorders or oro-esophageal abnormalities. Caution should be exercised when sevelamer carbonate tablets are used in these patients.

Hypocalcaemia/hypercalcaemia.

Patients with CKD may develop hypocalcaemia or hypercalcaemia. Sevelamer carbonate tablets do not contain calcium. Serum calcium levels should be monitored and elemental calcium should be given as a supplement in case of hypocalcaemia.

Metabolic acidosis.

Patients with chronic kidney disease are predisposed to metabolic acidosis. As part of good clinical practice, monitoring of serum bicarbonate levels is therefore recommended.

Peritonitis.

Patients receiving dialysis are subject to certain risks for infection specific to dialysis modality. Peritonitis is a known complication in patients receiving peritoneal dialysis and in a clinical study with sevelamer hydrochloride, a greater number of peritonitis cases were reported in the sevelamer group than in the control group. Patients on peritoneal dialysis should be closely monitored to ensure the correct use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis.

Anti-arrhythmic and anti-seizure medicinal products.

Caution should be exercised when prescribing sevelamer carbonate to patients also taking antiarrhythmic and anti-seizure medicinal products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hypothyroidism.

Closer monitoring of patients with hypothyroidism co-administered with sevelamer carbonate and levothyroxine is recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hyperparathyroidism.

Sevelamer carbonate is not indicated for the control of hyperparathyroidism. In patients with secondary hyperparathyroidism sevelamer carbonate should be used within the context of a multiple therapeutic approach, which could include calcium as supplements, 1,25 - dihydroxy Vitamin D3 or one of its analogues to lower the intact parathyroid hormone (iPTH) levels.

Use in the elderly.

No data available.

Paediatric use.

The safety and effectiveness of sevelamer carbonate in patients below the age of 18 years have not been established.

Effects on laboratory tests.

No data available.

Instructions to patients.

The contents of sevelamer carbonate tablets expand in water thus tablets should be swallowed intact and should not be crushed, chewed or broken into pieces prior to administration (see Section 4.2 Dose and Method of Administration).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interaction studies have not been conducted in patients on dialysis.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, decreased the bioavailability of ciprofloxacin by approximately 50% when co-administered with sevelamer hydrochloride in a single dose study. Consequently, sevelamer carbonate should not be taken simultaneously with ciprofloxacin.
Reduced levels of cyclosporin, mycophenolate mofetil and tacrolimus have been reported in transplant patients when co-administered with sevelamer hydrochloride without any clinical consequences (i.e. graft rejection). The possibility of an interaction cannot be excluded and a close monitoring of blood concentrations of cyclosporin, mycophenolate mofetil and tacrolimus should be considered during the use of combination and after its withdrawal.
During post-marketing experience, very rare cases of increased TSH levels have been reported in patients co-administered sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medications.
During post-marketing experience, very rare cases of increased phosphate levels have been reported in patients taking proton pump inhibitors co-administered with sevelamer carbonate.
Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from clinical trials. Special precautions should be taken when prescribing sevelamer carbonate to patients also taking these medications.
In interaction studies in healthy volunteers, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, had no effect on the bioavailability of digoxin, warfarin, enalapril or metoprolol.
In 14 healthy subjects receiving 2.4 g of sevelamer hydrochloride three times a day with meals for two days sevelamer did not alter the pharmacokinetics of a single dose of warfarin. In 14 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of warfarin.
In 19 healthy subjects receiving 2.4 grams of sevelamer hydrochloride three times a day with meals for 2 days, sevelamer did not alter the pharmacokinetics of a single dose of digoxin. In 18 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of digoxin.
Sevelamer carbonate is not absorbed and may affect the bioavailability of other medicinal products. When administering any medicinal product where a reduction in the bioavailability could have a clinically significant effect on safety or efficacy, the medicinal product should be administered at least one hour before or three hours after sevelamer carbonate, or the physician should consider monitoring blood levels.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data from the effect of sevelamer on fertility in humans. Sevelamer hydrochloride administered orally to male and female rats prior to and throughout mating, at doses up to 4.5 g/kg/day (more than 15 times the maximum tested human dose on a mg/kg basis for a 50 kg person) did not alter mating or fertility.
(Category B3)
The safety of sevelamer carbonate has not been established in pregnant or lactating women. Sevelamer carbonate should only be given to pregnant or lactating women if clearly needed and after careful risk/benefit analysis has been conducted for both the mother and foetus or infant.
Studies in animals have shown minimal reproductive toxicity when sevelamer was administered to rats at high doses.
There was no evidence of teratogenicity in rabbits or rats following oral administration of sevelamer hydrochloride during the period of organogenesis at respective doses 1.5 and 4.5 g/kg/day (5 and 15 times respectively on a mg/kg basis for a 50 kg human). In rats receiving doses of 1.5 and 4.5 g/kg/day during organogenesis, there was reduced or irregular ossification of foetal bones at exposures of 5 and 15 times the maximum tested human dose. In rabbits receiving 1 g/kg/day during organogenesis, there was an increase in early resorptions leading to a reduction in the number of live foetuses per liter at an exposure 3.3 times the maximum recommended human dose.
Oral administration of sevelamer hydrochloride to female rats throughout gestation and lactation at doses of 0.1 - 1 g/kg/day (exposure 0.3 - 3.3 times the maximum recommended human dose) did not affect the birth or growth of their offspring or their postnatal development.
In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of foetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred in mid- and high-dose groups (human equivalent doses less than the maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100, 500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group (human equivalent dose twice the maximum clinical trial dose).
Oral administration of sevelamer hydrochloride to female rats throughout gestation and lactation did not have any adverse effects on offspring (see Use in pregnancy).
No adequate and controlled studies have been conducted using sevelamer in nursing mothers. It is unknown whether sevelamer is excreted in human breast milk. The nonabsorbed nature of sevelamer indicates that excretion of sevelamer in breast milk is unlikely. Sevelamer carbonate tablets should only be used during breastfeeding if the potential benefit justifies the potential risks.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The safety of sevelamer (as either carbonate and hydrochloride salts) has been investigated in numerous clinical trials involving a total of 969 haemodialysis patients with treatment duration of 4 to 50 weeks (724 patients treated with sevelamer hydrochloride and 245 with sevelamer carbonate), 97 peritoneal dialysis patients with treatment duration of 12 weeks (all treated with sevelamer hydrochloride) and 128 patients with CKD not on dialysis with treatment duration of 8 to 12 weeks (79 patients treatment with sevelamer hydrochloride and 49 with sevelamer carbonate). The safety profile of sevelamer carbonate in patients not on dialysis was similar to the safety profile of the drug in patients on dialysis.
Data possibly or probably related to sevelamer from these studies are listed below by frequency. The reporting rate is classified as very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Table 4 provides a tabulated list of adverse reactions in CKD patients on haemodialysis (Study GD3-163-201). Patients received sevelamer carbonate 800 mg tablets and sevelamer hydrochloride 800 mg tablets for eight weeks each with meals. Adverse reactions occurring in ≥ 5% of patients are listed by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT).
The most frequently occurring (≥ 2% of patients) undesirable effects possibly or probably related to sevelamer were mainly in the gastrointestinal disorders system organ class (Table 5). Most of these adverse reactions were mild to moderate in intensity.

Post-marketing experience.

During post-marketing experience, the adverse events (listed by frequency) in Table 6 have been reported in patients receiving sevelamer carbonate although no direct relationship to sevelamer carbonate could be established.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

In CKD patients on dialysis, the maximum dose studied was 14.4 grams of sevelamer carbonate and 13 grams of sevelamer hydrochloride. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been given to normal healthy volunteers in doses of up to 14.4 grams per day for 8 days with no adverse effects.
There are no reported cases of overdose with sevelamer carbonate or sevelamer hydrochloride in patients. Since sevelamer is not absorbed, the risk of systemic toxicity is low.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Patients with end-stage renal disease (ESRD) retain phosphorus and can develop hyperphosphataemia. High serum phosphorus can precipitate serum calcium resulting in ectopic calcifications. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 4.46 (mmol/L)², there is an increased risk that ectopic calcification will occur. Hyperphosphataemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. An increase in parathyroid hormone (PTH) levels is characteristic of patients with chronic renal failure. Increased levels of PTH can lead to the bone disease osteitis fibrosa. A decrease in serum phosphorus may decrease serum PTH levels.
Sevelamer contains multiple amines separated by one carbon from the polymer backbone, which become partially protonated in the intestine and interact with phosphorus molecules through ionic and hydrogen bonding. By binding phosphorus in the gastrointestinal tract and decreasing absorption, sevelamer lowers the phosphorus concentration in the serum.
Sevelamer decreases the incidence of hypercalcaemic episodes as compared to patients using calcium based phosphate binders alone, probably because the product itself does not contain calcium.
Sevelamer carbonate was developed as a pharmaceutical alternative to sevelamer hydrochloride. Sevelamer carbonate is an anion exchange resin with the same polymeric structure as sevelamer hydrochloride in which carbonate replaces chloride as the counter ion. While the counter ions differ for the two salts, the polymer itself, the active moiety, is the same.
Sevelamer treatment also results in a lowering of low density lipoprotein (LDL) and total serum cholesterol levels by increasing faecal excretion of bile acids. Because sevelamer binds bile acids, it may interfere with normal fat absorption and thus may reduce absorption of fat soluble vitamins such as A, D and K. In clinical trials of sevelamer, both the mean total-cholesterol and LDL-cholesterol declined by 15-39%. This effect is observed after 2 weeks. Triglycerides, HDL cholesterol and albumin did not change.

Clinical trials.

The ability of sevelamer to control serum phosphorus in CKD patients on dialysis was predominantly determined from the effects of the hydrochloride salt to bind phosphate. Six clinical trials used sevelamer hydrochloride and three clinical trials used sevelamer carbonate.
The sevelamer hydrochloride studies include one double-blind, placebo controlled 2-week study (sevelamer N = 24); two open-label, uncontrolled, 8-week studies (sevelamer hydrochloride N = 220) and three active-controlled open-label studies with treatment durations of 8 to 52 weeks (sevelamer hydrochloride N = 256). The sevelamer carbonate studies include one double-blind, active-controlled, cross-over study with two 8-week treatment periods using sevelamer carbonate tablets (N = 79), one open-label, active-controlled, cross-over study with two 4-week treatment periods using sevelamer carbonate powder (N = 31) and one randomized, parallel, open-label study using sevelamer carbonate powder (N = 144) dosed once daily or sevelamer hydrochloride tablets (N = 73) dosed three times daily for 24 weeks. Six of the active-controlled studies are described here (three sevelamer hydrochloride and three sevelamer carbonate studies). In all clinical studies patients were instructed to take sevelamer with meals.

Sevelamer hydrochloride versus calcium acetate, cross-over study in haemodialysis patients (GTC-36-301).

In a cross-over study of sevelamer hydrochloride and calcium acetate, 84 ESRD patients on haemodialysis who were hyperphosphataemic (serum phosphorus > 1.94 mmol/L) following a 2-week phosphate binder washout period were randomised to receive either sevelamer hydrochloride for 8 weeks followed by calcium acetate for 8 weeks or calcium acetate for 8 weeks followed by sevelamer hydrochloride for 8 weeks. Treatment periods were separated by a 2-week phosphate binder washout period. Patients started on sevelamer hydrochloride capsules or calcium acetate tablets 3 times per day with meals. Over each 8-week treatment period, at three separate time points the dose of either agent could be titrated up one capsule or tablet per meal (3 per day) to control serum phosphorus. Sevelamer hydrochloride and calcium acetate both significantly decreased mean serum phosphorus by about 0.65 mmol/L (Table 7).

Figure 1 illustrates that the proportion of patients achieving a given level of serum phosphorus lowering is comparable between the two treatment groups. For example, about half the patients in each group had a decrease of at least 0.65 mmol/L at endpoint. Successful control of serum phosphorus in chronic kidney disease patients is multifactorial including reduction of dietary phosphate intake, removal of phosphate with dialysis and inhibition of intestinal phosphate absorption with phosphate binders. As seen in Figure 2, some of the patients in GTC-36-301 did not respond to sevelamer hydrochloride treatment. Not all patients achieve phosphorus control with sevelamer hydrochloride alone, especially at the doses administered in this study (average actual daily dose 4.3 g/day). Later studies which employed higher doses of sevelamer hydrochloride (i.e. GTC-49-301-average actual daily dose 6.5 g/day) had a better rate of phosphorus response.

Average daily consumption at the end of treatment was 4.9 g sevelamer hydrochloride (range of 0.0 to 12.6 g) and 5.0 g of calcium acetate (range of 0.0 to 17.8 g). During calcium acetate treatment, 22% of patients developed serum calcium ≥ 2.75 mmol/L on at least one occasion versus 5% for sevelamer hydrochloride (p < 0.05). Thus the risk of developing hypercalcaemia is less with sevelamer hydrochloride compared to calcium acetate.
Mean LDL cholesterol and mean total cholesterol declined significantly on sevelamer hydrochloride capsules treatment (-24% and -15% respectively). Neither LDL nor total cholesterol changed on calcium acetate treatment. Triglycerides, high-density lipoprotein (HDL) cholesterol, and albumin did not change on either treatment.
Similar reductions in serum phosphorus and LDL cholesterol were observed in an 8-week open-label, uncontrolled study of 172 end-stage renal disease patients on haemodialysis.

Sevelamer hydrochloride versus calcium in haemodialysis patients (GTC-49-301).

In a parallel study of sevelamer hydrochloride and calcium acetate or calcium carbonate, two hundred ESRD patients on haemodialysis who were hyperphosphataemic (serum phosphorus > 1.78 mmol/L) following a two-week phosphate binder washout period were randomised to receive sevelamer hydrochloride 800 mg tablets (N = 99) or calcium, either calcium acetate (N = 54) or calcium carbonate (N = 47). Seventy seven percent of sevelamer hydrochloride patients (N = 76) and 80% of the calcium patients (N = 81) completed the full 52 weeks of treatment with the major reason for dropout in the sevelamer hydrochloride group was gastrointestinal adverse events. Calcium acetate and calcium carbonate produced comparable decreases in serum phosphorus. At week 52, using last observation carried - forward, sevelamer hydrochloride and calcium both significantly decreased mean serum phosphorus (Table 8).

Figure 2, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment.

Average daily consumption at the end of the treatment was 6.5 g of sevelamer hydrochloride (range of 0.8 to 13 g) or approximately eight 800 mg tablets (range of 1 to 16 tablets), 4.6 g of calcium acetate (range of 0.7 to 9.5 g) and 3.9 g of calcium carbonate treatment, 34% of patients in the calcium group developed serum calcium corrected for albumin ≥ 2.75 mmol/L on at least one occasion versus 7% for sevelamer hydrochloride (p < 0.05). Thus the risk of developing hypercalcaemia is less with sevelamer hydrochloride compared to calcium salts.
Mean LDL cholesterol and mean total cholesterol declined significantly (p < 0.05) on sevelamer hydrochloride treatment (-32% and -20%, respectively) compared to calcium (+0.2% and -2%, respectively) triglycerides, HDL cholesterol, and albumin did not change.

Sevelamer hydrochloride versus calcium acetate in peritoneal dialysis patients (REN-003-04).

In a parallel study of sevelamer hydrochloride or calcium acetate in peritoneal dialysis patients, one hundred and forty three patients on peritoneal dialysis who were hyperphosphatemic (serum phosphorus ≥ 1.78 mmol/L) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride 800 mg tablets (N = 97) or calcium acetate (N = 46). Treatment for 12 weeks with sevelamer was non-inferior to calcium acetate in reducing serum phosphorus. There were statistically significant changes in serum phosphorus (p < 0.001) from baseline for both the sevelamer hydrochloride (0.52 mmol/L from 2.42 mmol/L) and calcium acetate (-0.58 mmol/L from 2.35 mmol/L) groups.
Average daily consumption at the end of treatment was 5.9 g for sevelamer hydrochloride (range of 0.8 to 14.3 g) and 4.3 g for calcium acetate (range of 1.7 to 9.0 g). During calcium acetate treatment, 18% of patients had a serum calcium corrected for albumin ≥ 2.75 mmol/L at the end of the study versus 2% for sevelamer hydrochloride (p = 0.001).
There appeared to be a trend for a decrease from baseline for total, LDL, and non-HDL cholesterol levels in patients receiving sevelamer hydrochloride. The long term impact of sevelamer hydrochloride on cardiovascular related morbidity and mortality is unclear.

Cross-over study of sevelamer carbonate 800 mg tablets and sevelamer hydrochloride 800 mg tablets (GD3-163-201).

Stage 5 CKD patients on haemodialysis were entered into a five-week sevelamer hydrochloride run-in period and 79 patients received, in random order, sevelamer carbonate 800 mg tablets and sevelamer hydrochloride 800 mg tablets for eight weeks each, with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6 g/day divided among meals for both treatments. Forty of those completing the cross-over portion of the study were entered into a two-week washout period during which patients were instructed not to take any phosphate binders; this confirmed the activity of sevelamer in this study. See Table 9.

Cross-over study of sevelamer carbonate powder and sevelamer hydrochloride tablets (SVCARB00205).

Stage 5 CKD patients on haemodialysis were entered into a four-week sevelamer hydrochloride run-in period and 31 patients received, in random order, sevelamer carbonate powder and sevelamer hydrochloride tablets for four weeks each with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6.0 g/day divided among meals for sevelamer carbonate powder and 6.4 g/day divided among meals for sevelamer hydrochloride tablets. See Table 10.

Sevelamer carbonate powder once a day versus sevelamer hydrochloride tablet three times a day dosing (GD3-199-301).

Stage 5 CKD patients on haemodialysis with a serum phosphate level of > 1.78 mmol/L after washout from baseline therapies were randomized in a 2:1 ratio to receive either sevelamer carbonate powder once-daily (N = 144) or sevelamer hydrochloride as a tablet with the dose divided three times per day (N = 73) for 24 weeks. The initial dose for the two groups was 4.8 g/day. At the end of the study, the total daily dose was 6.2 g/day of sevelamer carbonate powder once daily and 6.7 g/day of sevelamer hydrochloride tablets three times per day. A greater percentage of subjects on the once daily dose than three times per day regimen discontinued therapy prematurely, 35% versus 15%. The reasons for discontinuation were largely driven by adverse events and withdrawal of consent in the once daily dosing regimen. Serum phosphate levels and calcium-phosphate product were better controlled on the three times per day regimen than on the once daily regimen. Mean serum phosphorus decreased 0.66 mmol/L for sevelamer carbonate powder once daily and 0.96 mmol/L for sevelamer hydrochloride tablets three times per day.

5.2 Pharmacokinetic Properties

Absorption.

Pharmacokinetic studies have not been carried out with sevelamer carbonate in humans. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, is not absorbed from the gastrointestinal tract. A mass balance study using ¹⁴C-sevelamer hydrochloride in 16 healthy male and female volunteers showed that sevelamer is not systemically absorbed. No absorption studies have been performed in patients with renal disease.

Excretion.

In dogs, > 94% of [14C-]-sevelamer carbonate was excreted in the faeces within 24 hours and ≤ 0.07% was recovered in urine.

5.3 Preclinical Safety Data

Genotoxicity.

In an in vitro mammalian cytogenetics test with metabolic activation, sevelamer hydrochloride caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation assay. Based on the available evidence, sevelamer hydrochloride is considered unlikely to be genotoxic in vivo following oral administration.

Carcinogenicity.

Sevelamer hydrochloride was administered in the diet to rats and mice for two years. In mice and female rats, there was no increase in the incidence of tumours. In male rats, there was an increased incidence of transitional cell papillomas and transitional cell carcinomas in the urinary bladder at a dose of 3 g/kg/day, which is 10 times the maximum daily human dose (mg/kg basis) for a 50 kg person examined in clinical trials.
To investigate the mechanism of action of proliferative effects (development of urinary bladder transitional cell papilloma) noted previously in the rat study of sevelamer hydrochloride, sevelamer carbonate was administered to male rats by dietary admixture for a period of 13 weeks at nominal dose-levels of 250, 1000 or 4500 mg/kg/day followed by 6 week treatment free period. Sevelamer carbonate was well tolerated at all dose-levels. No treatment-related changes were seen in the macroscopic or microscopic examinations. The urine of the mid and high dose sevelamer carbonate groups contained significant levels of calcium oxalate crystals. Immunohistochemical analyses did not identify increased cell proliferation in the urinary bladder or kidneys. This study did not replicate the proliferative changes observed in the urinary tract in a previous study of sevelamer hydrochloride.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, crospovidone, hyprolose, silicon dioxide, zinc stearate, Opadry AMB complete film coating system OY-B-29000 Translucent (ARTG PI No. 106232), Opacode monogramming ink S-1-17823 Black (ARTG PI No. 12108).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Do not refrigerate. Protect from moisture. Keep the container tightly closed.

6.5 Nature and Contents of Container

ARX-Sevelamer tablets are packaged in white high-density polyethylene bottles (HDPE), with a child resistant polypropylene cap.
ARX-Sevelamer tablets are available in pack sizes of 30^#*, 180 and 270*.
^# Starter pack.
* Presentations currently not-marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Sevelamer carbonate tablets contain sevelamer, a non-absorbed phosphate binding cross-linked polymer, free of metal and calcium. Sevelamer is a white to off-white powder comprising of a partial carbonate salt with approximately 40% amine carbonate and 60% free base. Sevelamer carbonate is amorphous, hygroscopic and hydrophilic, but insoluble in water with a pH range of 8-10.5 as a 1% aqueous slurry.

Chemical structure.

The primary amine groups shown in the structure are derived directly from poly (allylamine hydrochloride). The cross-linking groups consist of two secondary amine groups derived from poly (allylamine hydrochloride) and one molecule of epichlorohydrin.
Molecular Formula: (C₃H₇N.nH₂CO₃)_810z (C₉H₁₈N₂O.nH₂CO₃)_95z where z = a large number.
Chemical Name: poly (allylamine-co-N,N'-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt.

CAS number.

845273-93-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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ARX-Sevelamer (was Sevelamer APOTEX)

Sevelamer carbonate

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ARX-Sevelamer (was Sevelamer APOTEX) 800 mg Tablets